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WO2000012512A1 - Derives porphyrine, leur utilisation en therapie photodynamique, et dispositifs medicaux les contenant - Google Patents

Derives porphyrine, leur utilisation en therapie photodynamique, et dispositifs medicaux les contenant Download PDF

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Publication number
WO2000012512A1
WO2000012512A1 PCT/GB1999/002864 GB9902864W WO0012512A1 WO 2000012512 A1 WO2000012512 A1 WO 2000012512A1 GB 9902864 W GB9902864 W GB 9902864W WO 0012512 A1 WO0012512 A1 WO 0012512A1
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compound
composition
formula
group
phenyl
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PCT/GB1999/002864
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English (en)
Inventor
William Guy Love
Michael John Cook
David Andrew Russell
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Destiny Pharma Limited
University Of East Anglia
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Priority claimed from GBGB9818789.1A external-priority patent/GB9818789D0/en
Priority claimed from GBGB9912971.0A external-priority patent/GB9912971D0/en
Application filed by Destiny Pharma Limited, University Of East Anglia filed Critical Destiny Pharma Limited
Priority to US09/786,139 priority Critical patent/US6630128B1/en
Priority to DE69922216T priority patent/DE69922216T2/de
Priority to JP2000567534A priority patent/JP5008793B2/ja
Priority to AT99943075T priority patent/ATE283271T1/de
Priority to EP99943075A priority patent/EP1107971B1/fr
Priority to AU56360/99A priority patent/AU765509B2/en
Priority to CA2341507A priority patent/CA2341507C/fr
Publication of WO2000012512A1 publication Critical patent/WO2000012512A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to compounds, compositions, apparatus and methods for treating a medical condition for which a photodynamic compound is indicated, particularly in the curative or prophylactic treatment of medical conditions such as atherosclerosis, cataracts, restenosis, secondary cataracts, endometrial ablation, bladder cancer, other cancers and proliferative diseases, inflammation and infection.
  • Photodynamic therapy is a method of treating a diseased tissue of a patient.
  • the surgical procedure involves administering a photodynamic agent to a patient, such as via an intravenous injection, and then irradiating the target diseased tissue with a separate light source.
  • the photodynamic agent following irradiation with light emits reactive oxygen species, such as singlet oxygen, which disrupt the surrounding cellular tissue.
  • US Patent No. 5594136 relates to texaphyrins supported on a matrix.
  • the matrix-supported texaphyrins may be used in the separation of neutral and anionic species, in applications concerning phosphate ester hydrolysis, magnetic resonance imaging and photodynamic therapy.
  • US Patent No. 5284647 relates to meso-tetraphenylporphyrin compounds which have a maximum of two substituents on the phenyl rings.
  • the present invention therefore seeks to provide improved compounds, compositions, apparatus and methods for treating a medical condition where photodynamic therapy is indicated and open the way for medical conditions which are not currently treated by photodynamic therapy.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent H, lower alkyl, lower alkenyl and lower alkynyl, the latter three of which are optionally substitoted or terminated by one or more substitoents selected from halo, cyano, nitro, lower alkyl, OR 10 , C(0)R ⁇ , C(0)OR 12 , C(0)NR 13 R 14 and NR 15 R 16 ;
  • M represents a metallic element or a metalloid element
  • Each Y 1 , Y 2 and Y 3 is independently absent or represents O;
  • Z is absent or represents lower alkylene
  • R 10 , R 11 , R 12 , R 13 , R 14 , and R 16 independently represent H or lower alkyl
  • R 15 represents H, lower alkyl, aryl or lower alkylaryl
  • R 17 , R 18 and R 19 independently represent H, lower alkyl, aryl or lower alkylaryl
  • R 20 represents H, lower alkyl, lower alkenyl or C(0)R 21 where R 21 represents an activating group for reaction to form an amide bond such as N-hydroxysuccinimide, N-hydroxybenzotriazole, or pentafluorophenyl ester; and
  • lower alkyl is intended to include linear or branched, cyclic or acyclic, C r C 20 alkyl which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkyl chain).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 may represent include C r C 18 alkyl, C r C 17 alkyl, C r C 16 alkyl, C r C 15 alkyl, C 2 -C 15 alkyl, C 3 -C 15 alkyl, C 4 -C 15 alkyl, C 5 -C 15 alkyl, C 6 -C 15 alkyl, C 7 -C 15 alkyl, C 8 -C 15 alkyl, C 8 -C 14 alkyl, C 8 -C 12 alkyl and C 8 -C 10 alkyl.
  • Preferred lower alkyl groups which R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 , R 16 , R 20 and R 23 may represent include C 6 , C 7 , C 8 , C 9 , C 10 , C ⁇ , C 12 , C 13 , C 14 , C 15 and C 16 alkyl.
  • Preferred lower alkyl groups which R 17 , R 18 and R 19 may represent include C r C 3 alkyl, especially methyl or ethyl.
  • lower alkenyl and lower alkynyl are intended to include linear or branched, cyclic or acyclic, C 2 -C 20 alkenyl and C 2 -C 20 alkynyl, respectively, each of which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkenyl or alkynyl chain).
  • lower alkenyl also includes both the cis and trans geometric isomers.
  • Lower alkenyl groups which R 1 , R 2 , R 3 , R ⁇ R 5 , R 6 , R 7 , R 8 , R 9 , R 20 and R 23 may represent include C 2 -C 18 alkenyl, C 2 -C 17 alkenyl, C 2 -C 16 alkenyl, C 2 -C 15 alkenyl, C 3 -C 15 alkenyl, C 4 -C 15 alkenyl, C 5 -C 15 alkenyl, C 6 -C 15 alkenyl, C 7 -C 15 alkenyl, C 8 -C 15 alkenyl, C 8 -C 13 alkenyl and C 8 -C 12 alkenyl, C 8 -C 10 alkenyl.
  • Preferred lower alkenyl groups which R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 20 , and R 23 may represent include C 6 , C 7 , C 8 , C 9 , C 10 , C ⁇ , C 12 , C 13 and C 14 alkenyl, especially C 10 alkenyl.
  • Lower alkynyl groups which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 20 and R 23 may represent include C 2 -C 18 alkynyl, C 2 -C 17 alkynyl, C 2 -C 16 alkynyl, C 2 -C 15 alkynyl, C 2 -C 14 alkynyl, C 3 -C 15 alkynyl, C 4 -C 15 alkynyl, C 5 -C 15 alkynyl, C 6 -C 15 alkynyl, C 7 -C 15 alkynyl, C 8 -C 15 alkynyl, C 8 -C 14 alkynyl, C 8 -C 13 alkynyl, C 8 -C 12 alkynyl and C 8 -C 10 alkynyl.
  • Preferred lower alkynyl groups which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 20 and R 23 may represent include C 6 , C 7 , C 8 , C 9 , C 10 , C n , C 12 , C 13 and C 14 alkynyl, especially C 10 alkynyl.
  • lower alkylene also includes linear or branched C, to C 20 alkylene which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkenyl chain).
  • Preferred lower alkylene groups which Z, V and S may represent include C 2 -C 20 alkylene, C 4 -C 20 alkylene, C 4 -C 18 alkylene, C 4 -C 16 alkylene, C 5 -C 16 alkylene, C 6 -C 16 alkylene, C 7 -C 16 alkylene, C 8 -C 16 alkylene, C 9 -C 16 alkylene, C l0 -C 16 alkylene, C 12 -C 16 alkylene and C 14 -C 16 alkylene.
  • lower alkylene represents an alkylene having an even number of carbon atoms, for example C 2 , C 4 , C 6 , C 8 , C 10 , C 12 , C 14 , C 16 , C 18 and C 20 alkylene, especially C 6 , C 10 , C 12 , C 14 , C 16 and C 20 alkylene.
  • aryl includes six to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substitoted by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR 10 , C(0)R n , C(0)OR 12 , C(0)NR 13 R 14 and NR 15 R 16 .
  • the term "metallic element” is intended to include a divalent or trivalent metallic element.
  • the metallic element is diamagnetic. More preferably, the metallic element is selected from Zn (II), Cu (II), La (III), Lu (III), Y (III), In (III) Cd (II), Mg (II), Al(lT ⁇ ) and Ru. Most preferably, the metallic element is Zn (II) or Mg (IT).
  • metal is intended to include an element having physical and chemical properties, such as the ability to conduct electricity, that are intermediate to those of both metals and non-metals.
  • metalloid element includes silicon (Si) and germanium (Ge) atoms which are optionally substitoted with one or more ligands.
  • metallic element and metalloid element include a metal element or a metalloid element having a positive oxidation state, all of which may be substitoted by one or more ligands selected from halo, OH, OR 23 wherein R 23 is lower alkyl, lower alkenyl, lower alkynyl, aryl or alkylaryl as defined above.
  • the term when X represents "S-] 2 " means the disulphide dimer, for example the disulphide dimer of the compound of formula I or the disulphide dimer of a photosensitizable compound as defined hereinafter.
  • the compound of formula I or the photosensitizable compound is then bonded through the sulphur atom to an insoluble support thus fomiing a thio ether or a disulphide linkage.
  • X represents "C(0)] 2 0" means the anhydride, for example the anhydride of the compound of formula I, the anhydride of an insoluble support or an anhydride of a photosensitizable compound as defined hereinafter.
  • Preferred compounds of the invention include those in which each Y 1 , Y 2 and Y 3 represents oxygen, or each Y 1 and Y 3 represents oxygen and each Y 2 is absent.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 represent lower alkyl and each Y 1 , Y 2 and Y 3 represents oxygen, or each Y 1 and Y 3 represents oxygen and each Y 2 is absent and one or more of R 1 , R ⁇ R 4 , R 6 , R 7 and R 9 (preferably all) represent lower alkyl and R 2 , R 5 and R 8 (preferably all) represent H.
  • Preferred compounds of the invention include those wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represent H or lower alkyl;
  • M represents a metallic element, a silicon atom, or a germanium atom
  • Each Y 1 , Y 2 and Y 3 represents oxygen, or each Y 1 and Y 3 represents oxygen and each Y 2 is absent;
  • Z is absent or represents lower alkylene.
  • More preferred compounds of the invention include those wherein:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represent linear or branched, cyclic or acyclic, C 6 -C 16 alkyl and each Y 1 , Y 2 and Y 3 represents oxygen; or
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 independently represent linear or branched, cyclic or acyclic, C 6 -C 16 alkyl, R 2 , R 5 and R 8 represent H, each Y 1 and Y 3 represents oxygen and each Y 2 is absent;
  • M represents Zn (II), La (III), Lu (III), Y (III), In (III), Cd (II), Mg (II),
  • Z represents lower alkylene having an even number of carbon atoms.
  • Particularly preferred compounds of the invention include those wherein
  • R 1 , R 2 , R 3 , R ⁇ R 5 , R 6 , R 7 , R 8 and R 9 independently represent, n-C 6 H 13 , n- C 8 H 17 , n-C 10 H 21 , n-C 12 H 25 , n-C 14 H 29 , or n-C 16 H 33 and each Y 1 , Y 2 and Y 3 represents oxygen; or R 1 , R 3 , R 4 , R 6 , R 7 and R 9 independently represent n-C 6 H 13 , n-C 8 H 17 , n-C 10 H 21 , n-C 12 H 25 , n-C 14 H 29 , or n-C 16 H 33 , R 2 , R 5 and R 8 represent H, each Y 1 and Y 3 represents oxygen and each Y 2 is absent;
  • M represents Zn (II) or Mg (II);
  • Z represents n-C 6 H 12 , n-C 8 H 16 , n-C 10 H 20 , n-C 12 H 24 , n-C 14 H 28 , n-C 16 H 32 , n-
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 represent n-C 6 H 13 , n-C 10 H 21 or n-
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 independently represent n-C 6 H 13 , n-C ⁇ 0 H 21 or n-
  • M represents Zn (II) or Mg (II);
  • Z represents n-C 6 H 12 , n-C 10 H 20 , n-C 12 H 24 , n-C 16 H 32 , (CH 2 ) 12 -(CH 2 ) 2
  • Most preferred compounds of the invention include the compounds of Examples 67 to 81 described hereinafter.
  • the reduction may be accomplished using methods which are well known to those skilled in the art.
  • the reduction may be accomplished with a mixture of potassium hydroxide, an aryl sulphonylhydrazide, such as -toluenesulphonylhydrazide, and pyridine at a temperatore of between 80 °C to 110°C, preferably a temperature of 100°C to 105°C (R Bonnett et al, Biochem J. (1989) 261, p277-280).
  • the reaction is performed using an appropriate metal salt, such as magnesium perchlorate or zinc acetate, in a suitable solvent (E Dietel et al, Journal of the Chemical Society, Perkin Transactions II, 1998, p 1357 to 1364.
  • an appropriate metal salt such as magnesium perchlorate or zinc acetate
  • the reaction may be performed using an anhydrous zinc salt such as Zn(OAc) 2 or ZnCl 2 in anhydrous tetrahydrofuran at reflux temperature of the reaction.
  • a compound of formula II may be prepared by conversion of the Z-F functional group of a compound of formula III:
  • reaction may be accomplished via formation of an isothiuronium salt, from a compound of formula III when F represents OH, using reagents and conditions which are well known to those skilled in the art (see I Chambrier et al., Synthesis, 1995, pl283 to 1286).
  • the Z-OH alcohol functionality group of a compound of formula III is first derivatised into a Z-OS0 2 R 22 group, wherein R 22 is lower alkyl or phenyl, both of which may be optionally substitoted by one or more substitoents selected from halo, cyano, nitro, lower alkyl, OR 10 , C(0)R ⁇ , C(0)OR 12 , C(0)NR 13 R 14 and NR 15 R 16 , using methods which are well known to those skilled in the art.
  • the Z-OH alcohol functionality compound of formula III may be mesylated by reaction with MeS0 2 Cl in an appropriate solvent, such as dichloromethane, at a temperatore of 10°C to 30°C.
  • the resultant mesylate group may then be displaced by reaction with thiourea to form an isothiouronium salt.
  • the reaction is performed in THF/ethanol solvent mixture which has optionally been deoxygenated, under reflux in the dark, preferably under an inert atmosphere of nitrogen.
  • a compound of formula II when X represents SH may be prepared by the basic hydrolysis of the thiouronium salt in a THF/ethanol solvent mixture, for example using aqueous sodium hydroxide, under reflux and under an inert atmosphere, such as a nitrogen atmosphere.
  • a compound of formula II when X represents S-] 2 may be prepared by the basic hydrolysis of the thiouronium salt in a THF/ethanol solvent mixture, for example using aqueous sodium hydroxide, at reflux temperatore of the reaction mixture under an oxygen atmosphere.
  • the reaction may be accomplished via conversion of the Z-OH alcohol functionality group of a compound of formula III into a Z-OS0 2 R 22 group, wherein R 22 is as previously defined.
  • the Z-OH alcohol functionality of the compound of formula III may be mesylated by reaction with MeS0 2 Cl.
  • the resultant mesylate group may then be displaced by reaction with the appropriate alkenoate, for example sodium butenoate, in an appropriate organic solvent such as THF under reflux.
  • a compound of formula III may be prepared by reaction of four molar equivalents of pyrrole with one molar equivalent of a compound of formula V:
  • the reaction is carried out under acidic conditions by methods known to those skilled in the art (R G Little et al, Journal of Heterocyclic Chemistry, 1975, Vol 12, p343).
  • an appropriate solvent such as an organic acid for example propionic acid
  • a mineral acid such as hydrochloric, hydrobromic, hydroiodic, or sulphuric acid
  • a Lewis acid such as zinc chloride or aluminium trichloride
  • the compounds of formula V may be prepared from reaction of a compound of formula IX: IX
  • the reaction is performed in a suitable organic solvent, such as methyl ethyl ketone or dichloromethane, under basic conditions, for example by using K 2 C0 3 , Na 2 C0 3 , pyridine or triethylamine, optionally at reflux temperatore of the reaction mixture.
  • a suitable organic solvent such as methyl ethyl ketone or dichloromethane
  • W represents OH
  • a suitable organic solvent such as dry tetrahydrofuran (THF) in the presence of triphenylphosphine and an azodicarboxylate, for example diisopropyl-azo dicarboxylate).
  • THF dry tetrahydrofuran
  • the compounds of formula VI, VII, and VIII may be prepared from reaction of a compound of formula X:
  • Y 1 , Y 2 and Y 3 are as previously defined before for a compound of formula III, or a suitably mono- or di-protected phenol derivative thereof, with a compound of formula R ! W, R 2 W, R 3 W, R 4 W, R 5 W, R 6 W, R 7 W, R 8 W or R ⁇ wherein R 1 , R 2 , R ⁇ R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as previously defined for a compound of formulae VI, VII and VIII, respectively, and W is a leaving group, such as halo.
  • the reaction is performed in a suitable organic solvent, such as methyl ethyl ketone or dichloromethane, under basic conditions, for example by using K 2 C0 3 , Na 2 C0 3 , pyridine or triethylamine, optionally at reflux temperatore of the reaction mixture.
  • a suitable organic solvent such as methyl ethyl ketone or dichloromethane
  • the present invention provides a composition comprising an insoluble support and a compound of the invention of formula I.
  • the insoluble support is also biocompatible.
  • insoluble we mean that the support does not dissolve or decompose in aqueous solution under normal physiological conditions over the intended timescale for photodynamic ability (ie reactive oxygen species production) of the photosensitizable compound.
  • the timescale would be relatively short for an insertable/removable medical device for example 1 to 180 minutes, or many years for semi-permanent or permanent implanted medical devices.
  • biocompatible we mean that the support is in a form that does not produce an adverse, allergic or other untoward reaction when administered to a human or animal in accordance with the invention.
  • the insoluble support enables the composition of the invention to be administered to a patient directly to the disease site without the need for administration by injection. This avoids the necessity for the photosensitizable compound to reach and accumulate at the target site, as is necessary with conventional photodynamic therapy, because the device is applied directly to the target site. Furthermore, the insoluble support eli ⁇ iinates or substantially reduces the dispersal and accumulation of the photosensitizable compound in non- target tissues, thereby minimising chemical toxicity and damage to healthy non-target tissue following irradiation with light of the appropriate wavelength or indeed from activation by sunlight and other environmental light sources. Moreover, unless deliberately left in the body, when the support is subsequently withdrawn, no compound of the invention is left in the body.
  • the solid support comprises polyethylene; polypropylene; polystyrene; poly acrylamide; poly amide; a resin for solid phase oligopeptide and/or oligonucleotide synthesis, such as a Merrifield resin; a natural or synthetic polysaccharide; a silicon derivative such as a functionalised silica, a glass, a silicone or a silicone rubber; an alumina; a noble metal, preferably a gold film optionally mounted on a glass surface; or a porous solid such as a controlled pore glass, a gel permeation material or a zeolite.
  • a resin for solid phase oligopeptide and/or oligonucleotide synthesis such as a Merrifield resin
  • a natural or synthetic polysaccharide such as a functionalised silica, a glass, a silicone or a silicone rubber
  • an alumina a noble metal, preferably a gold film optionally mounted on a glass surface
  • a porous solid such
  • the insoluble support may be flexible, such as a flexible membrane, or a rigid support.
  • the insoluble support is coated and/or impregnated with the photosensitizable compound. More preferably, the photosensitizable compound is fixed to the surface of the insoluble support, optionally via a covalent bond, and optionally includes a bifunctional spacer molecule to space the compound from the insoluble support.
  • a compound fixed to the surface of the insoluble support may be represented by formula XI:
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 , A-B, C-D, M, Z, Y 1 , Y 2 and Y 3 are as previously defined for a compound of formula I;
  • V is absent or represents lower alkylene or an alkylaryl group;
  • IS represents the insoluble support;
  • the group U of the insoluble support represents NHR 15 .
  • the group U of the insoluble support represents C0 2 R 20 .
  • the group U of the insoluble support represents Si(OR 17 ) 3 , SiR 18 (OR 17 ) 2 , SiR 18 R 19 (OR 17 ), Sihalo 3 , Sihalo 2 R 17 , or SihaloR 17 R 18 .
  • the insoluble support includes a noble metal.
  • composition of formula XI may also be represented by a compound of formula XII.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y 1 , Y 2 , Y 3 , Z, A-B, C-D and M are as previously defined for a compound of formula I
  • IS represents the insoluble support
  • V is absent or represents lower alkylene or an alkylaryl group
  • E represents alkylene, ether, amide, silyloxy, alkynyl, alkenyl, thioether, NR 15 , (CH 2 CH 2 ⁇ ) m , keto, ester, or phenyl wherein m represents 1 to 10 and R 15 is as previously defined hereinbefore.
  • a process for the preparation of a composition of formula XII which comprises reacting a compound of the invention of formula I as previously defined with a compound of formula XIII:
  • IS - V- U XIII wherein IS, V and U are as defined above.
  • the X groups present on a compound of the invention react with available groups, termed U, present on or previously inserted into, the insoluble support.
  • the reactive U group of the insoluble support may be either initially present or introduced by semi-synthesis (for example from materials derived from natural sources) or by ab initio chemical synthesis.
  • the photosensitizable compound may be linked to the polymeric support by using a dopant, such as an acrylic acid.
  • a dopant such as an acrylic acid.
  • the dopant may be incorporated into the polymeric support to provide a binding site for the photosensitizable compound or the dopant may be bonded to the photosensitizable compound and the resultant compound copolymerized with the polymeric support.
  • Reagents such as carbodiimides, l ,l '-carbonyldiimidazole, cyanuric chloride, chlorotriazine, cyanogen bromide and glutaraldehyde, and processes such as use of mixed anhydrides, reductive amination and metal- assisted cross-couplings of halogenated compounds with organometallic compounds may also be used to couple the photosensitizable compound to the insoluble support.
  • a composition for the in vivo delivery of a photosensitizable compound to a target tissue comprising a photosensitizable compound and a biocompatible insoluble support, wherein the photosensitizable compound comprises a macrocycle having at least four unsatorated five-membered nitrogen containing rings.
  • the term "unsatorated five-membered nitrogen containing ring” includes pyrrole, dihydropyrrole, pyrroline and isomers thereof.
  • the photosensitizable compound comprises a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixtore of any two or more of these, or a pharmaceutically acceptable derivative thereof.
  • the photosensitizable compound is a porphycene, a purpurin, a chlorophyll, a phthalocyanine, or a benzoporphyrin or a derivative of any of these compounds.
  • each of the four unsatorated five- membered nitrogen containing rings of the purpurin may be independently substituted with a lower alkyl, preferably an ethyl group.
  • Each of the phenyl rings of the phthalocyanine may independently include a sulphate, amino, nitro, hydroxy, or carboxyl group.
  • composition of the present invention comprising a photosensitizable compound and the insoluble support is preferably a compound of formula XIV:
  • PC represents a photosensitizable compound comprising a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixture thereof
  • IS represents the biocompatible insoluble support
  • the group U of the insoluble support represents NHR 15 .
  • the group U of the insoluble support represents C0 2 R 20 .
  • the group U of the insoluble support represents Si(OR 17 ) 3 , SiR 18 (OR 17 ) 2 , SiR 18 R 19 (OR 17 ), Sihalo 3 , Sihalo 2 R 17 , or SihaloR 17 R 18 .
  • the insoluble support includes a noble metal.
  • the photosensitizable compound includes a spacer group S to which the X group is attached, wherein S represents lower alkylene or an alkylaryl group.
  • the insoluble support includes a spacer group V to which the U group is attached, wherein V represents lower alkylene or an alkylaryl group.
  • the photosensitizable compound includes a metallic or a metalloid element bonded to a nitrogen atom, preferably to a pyrrole nitrogen atom, of the photosensitizable compound.
  • composition of the present invention comprising a photosentizable compound and the insoluble support may also be represented by a compound of formula XV.
  • E represents alkylene, ether, amide, silyloxy, alkynyl, alkenyl, thioether, NR 15 , (CH 2 CH 2 0) m , keto, ester, or phenyl, wherein m represents 1 to 10 and R 15 is as previously defined hereinbefore.
  • the present invention provides a process for the preparation of the composition of the invention comprising a photosensitizable compound and the insoluble support, which is preferably a compound of formula XIV or XV, as defined hereinbefore.
  • the insoluble support is coated and/or impregnated with the photosensitizable compound. More preferably, the photosensitizable compound is fixed to the surface of the insoluble support, optionally via a covalent bond and optionally includes a bifunctional spacer molecule to space the photosensitizable compound from the insoluble support.
  • the process for the preparation of a composition of the present invention comprises reacting a compound of formula XVI:
  • PC-S-X together represents the photosensitizable compound
  • X is as previously defined for a compound of formula XIV
  • PC represents a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixtore of any two or more of these
  • S is absent or represents lower alkylene or an alkylaryl group, with a compound of formula XVII:
  • IS-V-U together represents the insoluble support
  • U is as previously defined for a compound of formula XIV and V is absent or represents lower alkylene or an alkylaryl group.
  • the X groups of the photosensitizable compound react with available groups, termed U, present on or previously inserted into, the insoluble support.
  • the reactive X group of the photosensitizable compound and the reactive U group of the insoluble support may be either initially present or introduced by semi-synthesis (for example from materials derived from natural sources) or by ab initio chemical synthesis.
  • the photosensitizable compound may be linked to the polymeric support by using a dopant, such as an acrylic acid.
  • a dopant such as an acrylic acid.
  • the dopant may be incorporated into the polymeric support to provide a binding site for the photosensitizable compound or the dopant may be bonded to the photosensitizable compound and the resultant compound copolymerized with the polymeric support.
  • Reagents such as carbodiimides, l, -carbonyldiimidazole, cyanuric chloride, chlorotriazine, cyanogen bromide and glutaraldehyde, and processes such as use of mixed anhydrides, reductive amination and metal- assisted cross-couplings of halogenated compounds with organometallic compounds may also be used to couple the photosensitizable compound to the insoluble support.
  • monomers such as plastics made from unsatorated monomers (ie polyethylene, polypropylene, polyacrylates, polystyrene, polyamide) by processes such as free radical induced polymerisation to give either rigid or flexible insoluble polymeric matrices incorporating the desired photos
  • the photosensitizable compound when the photosensitizable compound represents a benzoporphyrin, a porphycene, a purpurin, a chlorophyll, an haematoporphyrin, an etiopurpurin, a phorbine, a verdin, a bacteriochlorin or a porphyrinogen having a group X representing C0 2 R 20 , the photosensitizable compound may be incorporated into a polymer having a NHR 15 group via amide bond formation by techniques which are well- known to those skilled in the art. Alternatively, the photosensitizable compound may be incorporated into a polymer having a carboxyl group by formation of a diamide type linkage using a bis-amino spacer.
  • the photosensitizable compound when the photosensitizable compound represents a porphycene having a group X representing NHR 15 , then the photosensitizable compound may be incorporated into a polymer having a C0 2 R 20 group via amide bond formation by techniques which are well- known to those skilled in the art. Alternatively, the photosensitizable compound may be incorporated into a polymer having an amino group by formation of a urea type linkage.
  • the photosensitizable compound when the photosensitizable compound is an haematoporphyrin, a phorbine or a porphyrinogen having a group X representing OH, then the photosensitizable compound may be incorporated into a functionalised silica group, such as a glass, by formation of a silyloxy linkage by methods well known to those skilled in the art.
  • the photosensitizable compound when the photosensitizable compound is a phorbine or a bacteriochlorin having a group X representing SH, then the photosensitizable compound may be bonded through the sulphur atom to the surface of a noble metal, such as metallic gold, thus forming a thio ether or disulfide linkage by methods well known to those skilled in the art.
  • a noble metal such as metallic gold
  • monomers such as plastics made from unsatorated monomers (ie polyethylene, polypropylene, polyacrylates, polystyrene, polyamide) or the photosensitizable compound may be incorporated into a polymer having a halo, C ⁇ CH
  • photosensitizable compound is derived from natural sources
  • advantage may be taken, for instance, of vinyl or carboxyl groups that are present in the native compound.
  • the isolation and/or synthesis of such photosensitizable compounds as previously defined for a compound of formula I are described for example in Bonnett R.
  • these and other functionalities may also be introduced into the photosensitizable compound using the appropriate chemistry on suitably protected precursor molecules.
  • carboxyl groups may be activated by conversion to the corresponding acid chloride, azide or activated ester and then incorporated into a construct by treatment with a polymeric matrix bearing nucleophilic substitoents.
  • compositions of the present invention comprising a photosensitizable compound and the insoluble support, which is preferably a compound of formula XIV or XV, where the photosensitizable compounds are synthesised for incorporation into the insoluble support to form a construct:
  • linkage of the photosensitizable compound to support matrices can be made through specific functional groups in multi-functional molecules.
  • the precursors may be synthesised using methods such as standard peptide chemistry described in the literature, for example in Houben Weyl, Methoden der Organischen Chemie, Parts 1 and 2, Vol 15. If necessary the carboxyl, amino, hydroxyl or thio functionalities of the precursor molecules may be protected using suitable reversible protecting groups.
  • protecting groups is fully described in "Protective Groups in Organic Chemistry” , edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis", 2 nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
  • the protected precursor molecules may be condensed with spacer molecules such as natural amino acids or other linkers by methods well known to those skilled in the art to give mixtores of derivatised protected photosensitizable compounds (for subsequent covalent linkage to preformed polymeric supports) which are enriched in the desired photosensitizable compound by appropriate choice of the relative amounts of the precursors and the conditions of the condensation reaction.
  • spacer molecules such as natural amino acids or other linkers
  • the desired photosensitizable compound may be isolated by chromatographic separation or crystallisation. These procedures can be optimised by judicious choice of the groups R combined with reversible optional protection of the function in the side-chain, if appropriate. At this point it can be advantageous to insert the metal atom into the macrocycle.
  • the functional group where appropriate, is activated or derivatised, and the macrocycle can be attached to a surface or copolymerised with a suitable comonomer. At various points in the sequence of reactions, it is possible to manipulate the photosensitizable compound structure when separation of any isomers is desired.
  • compositions of the invention are photodynamic as they emit reactive oxygen species, such as singlet oxygen or oxygen free radicals, following irradiation with light of the appropriate wavelength in the presence of oxygen. Consequently, the compositions of the invention are suitable for use in the curative and/or prophylactic treatment of a medical condition for which a photodynamic agent is indicated.
  • reactive oxygen species such as singlet oxygen or oxygen free radicals
  • compositions of the invention are suitable for use in the curative and/or prophylactic treatment of atherosclerosis; cataracts; restenosis; secondary cataracts; endometrial ablation; cancers such as bladder cancer; other proliferative diseases; bacterial infections such as Gram-positive cocci (eg Streptococcus), Gram-negative cocci (eg Neisseria), Gram-positive bacilli (eg Corynebacterium species) Gram-negative bacilli (eg Escherichia coli) acid-fast bacilli (eg a typical Mycobacterium) and including infections causing abscesses, cysts, arthritis, urinary tract infections, pancreatitis, pelvic inflammatory disease, peritonitis, prostatitis, vaginal infections, ulcers and other localised infections; actinomyces infections; fungal infections such as Candida albicans, Aspergillus and Blastomyces; viral infections such as HIV, encephalitis, gastro-enteritis, hae
  • the insoluble support is a noble metal film, preferably the noble metal is gold and the thickness of the film is 10 to 1000 nm.
  • X in a compound of the invention of formula I or a photosensitizable compound of formula XVI may represent SH or S-] 2 .
  • the compound of formula I or the photosensitizable compound is bonded through the sulphur atom to the surface of the metallic gold thus forming a thio ether or disulphide linkage.
  • a noble metal film coated with a compound of the invention or a photosensitizable compound may be prepared by immersing the film in a solution of a compound of formula I, wherein X represents SH or S-] 2 , in a suitable solvent, such as hexane, chloroform or dichloromethane, at room temperatore for up to 24 hours, optionally with stirring.
  • a suitable solvent such as hexane, chloroform or dichloromethane
  • the insoluble support includes a glass surface and X in the compound of formula I or X in the photosensitizable compound of formula XVI may represent Si(halo) 3 , particularly Si(Cl) 3 .
  • the photosensitizable compound is then bonded through the silicon atom to the glass surface
  • compositions of the invention may be fabricated into or coated on various medical devices and surgical implants, such as balloon catheters, vascular stents, intraocular lenses, orthopaedic implants, other artificial surgical implants, interfaces, artificial joints, surgical screws and pins.
  • medical devices such as balloon catheters, vascular stents, intraocular lenses, orthopaedic implants, other artificial surgical implants, interfaces, artificial joints, surgical screws and pins.
  • Each of the medical devices may also optionally include an integrated light delivery system.
  • a vascular stent is a permanent implant comprising a mesh-like tube which is used to maintain an open lumen within the blood vessels.
  • a vascular stent is made from metal, stainless steel, nickel, platinum, all of which are optionally coated with a polymer to increase biocompatability.
  • the stent may be made completely from polymers or plastics.
  • the stent is delivered to the target site in a blood vessel with a guide catheter, usually after a patient has been administered a bolus of heparin.
  • the guide catheter has a retractable sheath which shields the stent until it is at the target site.
  • the sheath is retracted to expose the stent.
  • the stent either self expands or it is expanded with an inflatable balloon of a balloon catheter. The stent delivery system, balloon and catheter are removed leaving the stent within the blood vessel.
  • An intraocular lens is a lens that is adapted to be fixed to the periphery of the iris or an opening in the capsular bag of the eye.
  • the lens is made from an acrylic polymer, such as polymethyl methacrylate or hydroxy ethyl methacrylate, optionally coated with a biocompatible polymer such as phosphorylcholine.
  • a suitable intraocular lens (IOL) is described in US 5716364, which is incorporated herein by reference.
  • the IOL is made of a polymeric material such as a polyolefin, for example polypropylene.
  • the coating is a molecular monolayer that partially or totally coats the surface of the medical device.
  • the coating may be fixed to the medical device by forming a bond between the -ZX functional group of the compound of the invention of formula I or a photosensitizable compound of formula XVI and the reactive U functional groups of the insoluble support as previously defined.
  • the coating may be formed by reacting the compounds or compositions of the invention with the polymeric precursors of a medical device prior to formation of the medical device.
  • the medical device when the medical device comprises a silica based polymer optionally having reactive or functionalised silica groups, such as a silicone polymer, the medical device also acts as the insoluble support and it may be coated and/or impregnated by direct reaction with a compound of the invention of formula I or a photosensitizable compound of formula XVI.
  • the compound of the invention or the photosensitizable compound is bonded to the silicone polymer with one of the linkages as previously disclosed herein.
  • the medical devices enable the compounds of the invention and the photosensitizable compounds to be delivered to a particular target tissue.
  • the target cells are the smooth muscle cells on the blood vessel lumen surface, and inflammatory cells such as macrophages
  • the target cells are the lens epithelial cells on the inner surface of the capsular bag which are typically aggregated around the periphery of the capsular bag.
  • This site specific delivery reduces or substantially eliminates undesirable side-effects associated with photodynamic agents residing in and accumulating in non-target tissues.
  • This increases patient compliance as a patient who has been treated with a medical device of the present invention only needs to shield the treated tissue from exposure to light, rather than other parts of the body which may be necessary with photodynamic agents having no site specific delivery system.
  • the coating of the medical device emits reactive oxygen species, such as singlet oxygen, which travel a distance of between 50 nm and 5 nm (micrometers) from the device depending on the composition of the medium surrounding the device.
  • reactive oxygen species such as singlet oxygen
  • the medium is a biological tissue
  • the reactive oxygen species travel between 10 and 50 nm from the device
  • the reactive oxygen species travel approximately 1 to 5 ⁇ m from the device when the medium is a saline solution
  • even greater distances 10 to 100 ⁇ m can be achieved in other liquids, alcohols, acetone and aqueous mixtores thereof.
  • Each of the medical devices may also include a fluid delivery system for delivering desired medium to the coating of the device.
  • a fluid delivery system for delivering desired medium to the coating of the device.
  • the distance the reactive oxygen species emitted from the devices of the present invention may be controlled accurately. This further reduces the undesirable side-effects associated with reactive oxygen species interacting with non-target tissue and thereby further increases patient compliance.
  • the material introduced into the body will be sterile and may also be non-pyrogenic. Sterility is typically achieved by conventional temperature, pressure, radiation or chemical sterilisation treatment techniques, preferably during the manufacture of the devices.
  • the present invention provides methods for treating or preventing cataracts, secondary cataracts, bladder cancers, restenosis, atherosclerosis, endometrial ablation, other cancers and proliferative diseases, inflammation and infection using the medical devices of the invention.
  • the present invention provides a method of producing light-induced singlet oxygen which comprises irradiating a compound or composition of the invention with light of the appropriate wavelength preferably 500 to 800 nm, in the presence of oxygen.
  • Figure 1 is a longitudinal cross-section of a preferred balloon attached to a catheter.
  • Figure 2 is a typical decay and fitted curve for the title compound of Example 78 in toluene excited at 355 nm using a pulse energy of 365 ⁇ J.
  • Figure 3 is a plot showing the linear relationship between the singlet oxygen emission intensity and the laser energy for the title compound of Example 78 and meso-tetraphenyl porphyrin (TPP).
  • Figure 1 shows a preferred embodiment of the invention comprising a balloon 1 having a surface coating 2 of a photodynamic compound or composition, an inflation port 3 and a two-way valve (not shown) to enable the balloon to be selectively inflated and deflated.
  • the balloon is preferably made from an elastomeric material, such as a flexible silicone polymer, and the coating is fixed to the balloon with linkage as described herein before.
  • the balloon is attached to a first end of a catheter 4.
  • a second end of the catheter includes means for receiving a pressure controlled inflation device 5, such as a standard Luer pressure tight connector having a stopcock.
  • the pressure controlled inflation device 5 is a normal syringe used in standard angioplastic and intraocular procedures with balloon catheters.
  • the syringe has an accurate graduation for measuring the volume of fluid injected into the balloon. It may also be optionally fitted with a pressure gauge. In use, pressure and volume measurements enable the balloon to be fully inflated at the target site whilst reducing the risk of damaging the surrounding non-target healthy tissue.
  • the first end of the catheter terminates in an injection means for filling the balloon with a filler material which is preferably a biocompatible fluid, such as sterile water.
  • a filler material which is preferably a biocompatible fluid, such as sterile water.
  • the catheter includes a fluid delivery system (not shown) for delivering a desired medium to the coating 2.
  • a light source preferably a fibre optic cable 6, extends throughout the length of the catheter and into the interior of the balloon 1 terminating with means for distributing light 7 in the balloon.
  • Air is removed from the apparatus before commencing the surgical operation by connecting the syringe, typically a 30ml syringe, to the Luer pressure tight connector, opening the stopcock and withdrawing the syringe piston.
  • the stopcock is closed and the syringe removed. The apparatus is now ready for use.
  • a pressure controlled inflation device preferably a 30ml syringe containing sterile water with no air bubbles and fitted with a pressure gauge, is attached to the luer fitting, the stopcock is opened and the balloon 1 inflated to a specific volume and/or pressure with the sterile water.
  • the required volume/pressure for inflation of the balloon can be determined by routine trial and error testing by a skilled person.
  • a light source is operated so that light of the appropriate wavelength, typically 500 to 800nm, passes through the fibre optic cable into the interior of the balloon.
  • the coating 2 absorbs the light and emits singlet oxygen radicals in the vicinity of the balloon, typically within a radius of between 50nm and 5 ⁇ m from the balloon.
  • the fluid delivery system may be used to deliver a desired fluid into the space 9 between the coating 2 and the target tissue 8, thereby enabling the user to vary and control the distance the singlet oxygen species are emitted from the balloon 1.
  • the singlet oxygen radicals induce molecular and cellular destruction of the target tissue.
  • Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electrospray interface (FAB-MS).
  • the matrix-assisted laser desorption/ionization mass spectra of the porphyrins were obtained using a dithranol matrix.
  • FAB-MS spectra were obtained using a 3-nitrobenzyl alcohol (NOB A) matrix.
  • NOB A 3-nitrobenzyl alcohol
  • ⁇ -NMR spectra were measured at 60MHz on a Jeol JNM-PMX60 spectrometer, at 270MHz on a Jeol EX 270 spectrometer and at 300MHx on a Varian Gemini-300 spectrometer in CDC1 3 using TMS as an internal reference.
  • Ultraviolet/visible spectra of solutions of compounds in tetrahydrofuran (THF) or toluene were measured using a Hitachi U-3000 spectrophotometer or a ATI-Unicam UV-2 spectrophotometer.
  • Reflectance-absorbance infra red (RAIR) spectra were recorded on a BIO- RAD FTS 165 spectrophotometer.
  • Fluorescence emission spectra were recorded using a Spex Fluorolog 3 spectrophotometer at an excitation wavelength of 355nm, emission at 550 to 800nm, with a bandpass of 2nm.
  • the singlet oxygen quantum yields were determined by the direct measurement of singlet oxygen phosphorescence at 1270nm.
  • Samples were excited using the third harmonic of a Q-s witched Nd:YAG (neodymium: yttrium-aluminium-garnet) Spectra Physics GCR-150-10 laser, operating at an excitation wavelength of 355nm.
  • a small fraction of the laser output was passed through a solution state filter containing aqueous cobalt (II) sulphate (CoS0 4 ) to remove residual 532 and 1064nm radiation and then down a 8mm diameter liquid light guide (Oriel).
  • II cobalt
  • CoS0 4 8mm diameter liquid light guide
  • the end of the light guide was held against a 1cm x 1cm fluorescence cuvette (Hellma) holding the sample.
  • the incident laser energy for each measurement was determined using a pyroelectric detector held behind the sample. This detector was calibrated at the start of the experiment using a second calibrated energy meter (Gentec ED 100).
  • the laser energy was adjusted by placing cells containing aqueous sodium nitrite between the CoS0 4 filter and the light guide. Typical pulse energies used were in the range of 25-500 ⁇ J per pulse. Shot to shot noise was estimated to be ⁇ 10% and sets of 20 shots gave an average value within ⁇ 3 % .
  • Phosphorescence from the sample was collected and passed through an interference filter centred at 1270nm available from (Infra Red Engineering Ltd) and then focused onto the active area of a liquid nitrogen cooled germanium photodiode (North Coast EO-817P).
  • the output from this device was AC coupled to a digital oscilloscope (Tektronix TDS-320) which digitised and averaged the transients. Typically 20 laser shots were used for each sample. The averaged data was transferred to a PC where it was stored and analysed.
  • the title compounds of Examples 2 to 8 represent compounds of formula V
  • the title compounds of Examples 9 to 14 represent compounds of formula VI, VII and VIII
  • the title compounds of Examples 28 to 40 represent compounds of the formula III
  • the title compounds of Examples 54 to 66 represent compounds of formula II
  • the title compounds of Examples 67 to 81 represent compounds of formula I.
  • 1,12-Dodecanediol 50g, 0.25mol
  • hydrogen bromide 48% 220ml
  • petroleum ether b.p. 80-100°C
  • Example 6 from 4-(6-hydroxy-hexyloxy)-benzaldehyde (see Example 3 above). After addition of the reaction mixtore to water, the title compound was obtained as a yellow oil. The oil was extracted with diethyl ether, the etheral extract was washed with aqueous K 2 C0 3 , brine, and dried over MgS0 4 , filtered and the solvent removed under reduced pressure.
  • Example 6 The title compound was prepared as described in Example 6 from 4-(16- hydroxy-hexadecyloxy)-benzaldehyde (see Example 4 above). The title compound was obtained as an oil.
  • the solid reaction product was collected by filtration and washed with methyl ethyl ketone (Soxhlet). The filtrate was evaporated under reduced pressure to give the title compound as a red oil which was crystallised from acetone.
  • Example 15 above from 3,4,5-trihexyloxy-benzaldehyde (see Example 10) acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 15 above from 3,4,5-trihexadecyloxy-benzaldehyde (see Example 11), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 15 above from 3,4,5-tridecyloxy-benzaldehyde (see Example 9), acetic acid 16-(4-formyl-phenoxy)-hexadecyl ester (see Example 8) and pyrrole.
  • Example 15 above from 3,5-dihexyloxy-benzaldehyde (see Example 12), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 25 above from 3,5-dihexyloxy-benzaldehyde (see Example 12), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 25 above from 3,5-dihexyloxy-benzaldehyde (see Example 12), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 15 above from 3,5-didecyloxy-benzaldehyde (see Example 13), acetic acid 6-(4-formyl-phenoxy)-hexyl ester (see Example 7) and pyrrole.
  • Example 24 above from 3,5-didecyloxy-benzaldehyde (see Example 13), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
  • Example 28 above from 5-[4-(6-acetyloxy-hexyloxy)-phenyl]-10, 15,20- tris-(3,4,5-trihexyloxy-phenyl)-porphyrin (see Example 17).
  • Example 28 above from 5-[4-(6-acetyloxy-hexyloxy)-phenyl]-10, 15,20- tris-(3,4,5-tridecyloxy-phenyl)-porphyrin (see Example 18).
  • Example 28 above from 5-[4-(6-acetyloxy-hexyloxy)-phenyl]-10, 15,20- tris-(3,4,5-trihexadecyloxy-phenyl)-porphyrin (see Example 19).
  • Example 28 above from 5-[4-(6-acetyloxy-hexyloxy)-phenyl]-10, 15,20- tris(3,5-didecyloxy-phenyl)-porphyrin (see Example 25).
  • Example 41 above from 5-[4-(12-hydroxy-dodecyloxy)-phenyl]-10, 15,20- tris-(3,4,5-trihexyloxy-phenyl)-porphyrin (see Example 29).
  • Example 41 above from 5-[4-(12-hydroxy-dodecyloxy)-phenyl]-10, 15,20- tris-(3,4,5-trihexyloxy-phenyl)-porphyrin (see Example 33).
  • Example 41 above from 5-[4-(12-hydroxy-dodecyloxy)-phenyl]-10, 15,20- tris-(3,4,5-trihexadecyloxy-phenyl)-porphyrin (see Example 34).
  • Example 41 above from 5-[4-(12-hydroxy-dodecyloxy)-phenyl]-10, 15,20- tris-(3,5-dihexyloxy-phenyl)-porphyrin (see Example 37).
  • the tide compound was prepared according to the method described in
  • Example 41 above from 5-[4-(12-hydroxy-dodecyloxy)-phenyl]-10, 15,20- tris-(3,5-dihexadecyloxy-phenyl)-porphyrin (see Example 40).
  • Analytical grade potassium hydroxide (lOOg) was dissolved in Millipore ® water (lOOml) and the solution was made up to 250ml with Distol grade methanol.
  • Gold deposition A layer of gold (ca. 45nm) was deposited on the slides using an Edwards 306 vacuum evaporator. A thin layer of chromium (ca. lnm) was initially deposited on the slides prior to the deposition of the gold to improve the adhesion of the gold to the slide.
  • Procedure 1 Components for MED-6640 film preparation were obtained from Nusil Technology-Europe. Solution A (1.05ml) and solution B (1ml) were mixed with stirring. The solution of the respective po ⁇ hyrin of Examples 69 to 81 (see above) in xylene (50 ⁇ l) was added. Portions of the mixtore were deposited onto microscope cover slips (13mm diameter) which were placed in an oven and heated to 40 °C for 2hrs. The temperatore was gradually raised to 150°C and the slides were kept at this temperatore for 15mins and then allowed to cool.
  • Procedure 2 The procedure 1 was repeated using solution A (1.025ml), solution B (1ml) and the solution of the respective po ⁇ hyrin in xylene (25 ⁇ l).
  • TPP meso-tetraphenylpo ⁇ hyrin
  • Zn TPP zinc tetraphenylpo ⁇ hyrin
  • the fluorescence quantom yield for each of the title compounds of Examples 67 to 81 are listed in Table 1; values for Zn TPP and Mg TPP are included in Table 1 for reference but they were not measured in this work. Table 1. Fluorescence Quantum Yields
  • a stock solution of each of the title compounds of Examples 67 to 81 was prepared by dissolving a small sample of the respective title compound in approximately 5ml of toluene (Fisher Scientific, Analytical grade). The exact concentrations of the stock solution was not dete ⁇ nined.
  • a working solution of each of the title compounds of Examples 67 to 81 was prepared by diluting the respective stock solution with toluene to give an absorbance of 0.100 ⁇ 0.005 at 355nm when placed in a ultraviolet/visible spectrometer (ATI-Unicam UV-2) compared to a reference cell containing the pure toluene solvent.
  • the ultraviolet/visible spectrum of each sample was also recorded over the range 300-700nm.
  • the final concentration of each of the respective working solutions was estimated by reference to the determined UV extinction coefficient; each working solution had a concentration in the range 5-10 ⁇ mol dm "3 .
  • a plot of A versus the incident laser energy was drawn for each sample and the slope deteraiined.
  • the slope of such a graph is proportional to the singlet oxygen quantom yield.
  • An example of a plot showing the linear relationship between the singlet oxygen emission intensity and the laser energy for the title compound of Example 78 and meso- tetraphenylpo ⁇ hyrin (TPP) is shown in Figure 3.
  • the experiments were carried out using batches of 5 samples of the working solution of each of the title compounds of 67 to 81 plus one reference sample meso-tetraphenylpo ⁇ hyrin (TPP). Each run was repeated at least once. The data sets obtained for each sample were within ⁇ 5 % of the mean value.
  • the dominant sources of error in the experiment include the shot-to-shot fluctuations in the laser and the difference in absorbances of the samples at the excitation wavelength.
  • the values have an error of ⁇ 10% .
  • the photosensitizable mixtore described above was deposited on a balloon shaped glass former and placed in an oven and heated to 40 °C for 2 hours.
  • the temperatore was gradually raised to 150°C, maintained at 150°C for 15 minutes and then allowed to cool.
  • the balloon was removed from the former, and the neck and the inflation port of the balloon adapted for engagement with a catheter.
  • a standard silicon based polymeric catheter balloon was sprayed coated with the photosensitizable mixtore described above.
  • the coating was cured as described in Procedure 1 to form a balloon having a molecular monolayer coating of the photosensitizable compound.
  • a polymeric intraocular lens was spray coated with the photosensitizable mixture of Example 86 above and the coating cured as described in Example 86 to form an intraocular lens having a molecular monolayer coating of the photosensitizable compound.
  • a polymeric vascular stent was spray coated with the photosensitizable mixture of Example 86 above and the coating cured as described in Example 86 to form a stent having a molecular monolayer coating of the photosensitizable compound.
  • a layer of gold (approximately 45 nm) was deposited on a metallic vascular stent using an Edwards 306 vacuum evaporator.

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Abstract

La présente invention concerne des composés de formule (I), dans laquelle R?1, R2, R3, R4, R5, R6, R7, R8, R9, X,Y1, Y2, Y3¿, Z, M, A-B et C-D ont les significations données dans la description, qui sont utiles dans des conditions médicales de traitement pour lesquelles un composé photodynamique est requis. La présente invention concerne aussi des compositions, un dispositif et des procédés de traitement destinés à des conditions médicales de traitement pour lesquelles un composé photodynamique est requis.
PCT/GB1999/002864 1998-08-28 1999-08-31 Derives porphyrine, leur utilisation en therapie photodynamique, et dispositifs medicaux les contenant WO2000012512A1 (fr)

Priority Applications (7)

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US09/786,139 US6630128B1 (en) 1998-08-28 1999-08-31 Porphyrin derivatives their use in photodynamic therapy and medical devices containing them
DE69922216T DE69922216T2 (de) 1998-08-28 1999-08-31 Porphyrin derivate, ihre verwendung in der photodynamischen therapie und diese enthaltende medizinische geräte
JP2000567534A JP5008793B2 (ja) 1998-08-28 1999-08-31 ポルフィリン誘導体、光力学療法におけるそれらの使用およびそれらを含有する医療装置
AT99943075T ATE283271T1 (de) 1998-08-28 1999-08-31 Porphyrin derivate, ihre verwendung in der photodynamischen therapie und diese enthaltende medizinische geräte
EP99943075A EP1107971B1 (fr) 1998-08-28 1999-08-31 Derives porphyrine, leur utilisation en therapie photodynamique, et dispositifs medicaux les contenant
AU56360/99A AU765509B2 (en) 1998-08-28 1999-08-31 Porphyrin derivatives, their use in photodynamic therapy and medical devices containing them
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